Patients with mutations of the THRA gene exhibit erythroid disorders. The molecular pathogenesis underlying erythroid abnormalities is poorly understood. In Thra1PV/+ mice expressing a dominant negative mutant TRalpha1PV, we found abnormal red blood cell indices similar to patients. Total bone marrow cells, the clonogenic potential of erythrocytic progenitors, and terminal differentiation of erythrocytes were markedly decreased in Thra1PV/+ mice. As far as we know, our study is the first study to show that Gata-1, a key erythroid gene, was directly positively regulated by TRalpha1. The erythroid defects in Thra1PV/+ mice were due, at least partly, to the TRalpha1PV-mediated suppression of the Gata-1 gene and its down-stream target genes. Over-expression of Gata-1 rescued impaired terminal differentiation. Our studies elucidated molecular mechanisms by which TRalpha1 mutants caused erythroid disorders in patients. The present study suggests that therapies aimed at GATA1 could be tested as a potential target in treating erythroid abnormalities in patients.